ROLE OF MALATE, LACTATE, AND ALANINE IN BRAIN METABOLISM AND TRAFFICKING

我们假设支链氨基酸（BCAA）水平升高 Maple患者脑中的α-酮酸（BCKA） 糖尿病肾病（MSUD）改变了氨基酸的释放和摄取， 影响大脑的能量代谢，破坏正常的细胞间 运输，并改变通过参与氨基酸 神经递质合成 BCAA和BCKA直接影响 谷氨酸、谷氨酰胺和天冬氨酸在脑中合成 作为氮供体或受体。 这些扰动可能导致 谷氨酸、GABA和天冬氨酸的显著减少， MSUD患者的大脑。谷氨酸水平的变化 及其相关的氨基酸与急性和长期 神经元损伤和脑功能异常。大型运输 大脑中的中性氨基酸也可能受到影响，因为它们共享 BCAA的共同携带者。在体内的主要目标之一是 微透析研究的目的是建立BCAA和BCKA 改变灌流大鼠间质中氨基酸的水平 BCAA或BCKA。在那里，这些研究将平行进行， 完整的大鼠大脑和培养的脑细胞。第二个目标 体内微透析研究是为了测量BCAA和BCKA的作用 对葡萄糖、谷氨酸和谷氨酰胺的氧化代谢的影响。 我们有 在体内证明α-酮异己酸刺激葡萄糖， 谷氨酸和谷氨酰胺氧化。 后者正在由一个 微透析法测量局部氧化新方法 葡萄糖和替代脑底物，在完整的大鼠脑中的14CO2。 竞争底物、脑区和MSUD代谢物对 将分析衬底氧化以确定 个别底物的氧化代谢。体内微透析 将结果与培养的星形胶质细胞中的平行研究进行比较， 皮质神经元、小脑颗粒细胞和混合细胞培养物中。 拟议中的研究将探讨过量水平的机制， BCAA和BCKA在细胞水平上影响大脑功能， 影响正常的智力发育这些研究的结果 应提供有关MSUD病因的有价值信息，并提供 临床方法的指导方针。

We hypothesize that elevated levels of branched chain amino acids (BCAA) and their alpha-keto acids (BCKA) in the brain of patients with Maple Syrup Urine Disease (MSUD) alters the release and up take of amino acids, affects energy metabolism of the brain, disrupts normal intercellular trafficking, and alters the flux through enzymes involved in amino acid neurotransmitter synthesis. BCAA and BCKA have a direct effect on the synthesis of glutamate, glutamine and aspartate in brain by their action as a nitrogen donor or acceptor. These perturbations may result in the pronounced decrease of glutamate, GABA, and aspartate reported in the brain of MSUD patients at autopsy. Alterations in the levels of glutamate and its related amino acids have been associated with both acute and long term neuronal damage and abnormal brain function. Transport of large neutral amino acids in brain may also be affected since they share a common carrier with BCAA. One of the major goals of the in vivo microdialyis studies is to establish the mechanisms by which BCAA and BCKA alter the level of amino acids in the interstitial space of rats perfused with BCAA or BCKA. There, these studies will be performed in parallel in the intact rat brain and in cultured brain cells. The second goal of the in vivo micro dialysis studies is to measure the effects of BCAA and BCKA on the oxidative metabolism of glucose, glutamate and glutamine. We have demonstrated in vivo that and alpha-ketoisocaproate stimulates glucose, glutamate and glutamine oxidation. The latter is being studied by an innovative adaptation of microdialysis to measure focal oxidation of glucose, and alternate brain substrates, to 14CO2 in the intact rat brain. The effect of competing substrates, brain region, and MSUD metabolites on substrate oxidation will be analyzed to determine the compartmentation of oxidative metabolism for individual substrates. The in vivo micro dialysis results will be compared to parallel studies in cultured astrocytes, cortical neurons, cerebellar granule cells, and in mixed cell cultures. The proposed studies will explore the mechanisms by which excessive levels of BCAA and BCKA affect brain function at the cellular level, thereby compromising normal mental development. The results of these studies should provide valuable information about the etiology of MSUD and provide guidelines for clinical approaches to this condition.